Abstract
Autophagy is a catabolic process involved in cellular homeostasis. Autophagy is increased above homeostatic levels by chemotherapy, and this can either promote or inhibit tumor growth. We previously demonstrated that aerosol gemcitabine (GCB) has a therapeutic effect against osteosarcoma (OS) lung metastases. However, some tumor cells failed to respond to the treatment and persisted as isolated lung metastasis. Here, we examined the mechanisms underlying the dual role of chemotherapy-induced autophagy in OS and sought to identify biomarkers to predict OS response to treatment. In this study, we demonstrate that treatment of various OS cells with GCB induced autophagy. We also showed that GCB reduces the phosphorylation of AKT, mTOR and p70S6K and that GCB-induced autophagy in OS can lead to either cell survival or cell death. Blocking autophagy enhanced the sensitivity of LM7 OS cells and decreased the sensitivity of CCH-OS-D and K7M3 OS cells to GCB. Using a kinase array, we also demonstrated that differences in the phosphorylated heat shock protein 27 (p-HSP27) expression in the various OS cell lines after treatment with GCB, correlates to whether chemotherapy-induced autophagy will lead to increase or decrease OS cells sensitivity to therapy. Increased p-HSP27 was associated with increased sensitivity to anticancer drug treatment when autophagy is inhibited. The results of this study reveal a dual role of autophagy in OS cells sensitivity to chemotherapy and suggest that p-HSP27 could represent a predictive biomarker of whether combination therapy with autophagy modulators and chemotherapeutic drugs will be beneficial for OS patients.
Highlights
Osteosarcoma (OS) is the most common primary malignant bone tumor
Using the same approach, we found that inhibition of autophagy in CCH-OS-D and K7M3 OS cells significantly decreased the sensitivity of these cells to GCB, as demonstrated by an increase in cell viability and a decrease in cleaved caspase 3 (Figures 6 and 7), confirming the opposing effect of GCB-induced autophagy in the CCH-OS-D and K7M3 OS cells as compared to the LM7 cells
These results are consistent with our published work where we demonstrated that treatment of DLM8 and K7M3 OS cells with CPT, a different chemotherapeutic agent, induced autophagy and that blocking autophagy in these cells led to survival in the DLM8 cells and death in the K7M3 cells [12]
Summary
Osteosarcoma (OS) is the most common primary malignant bone tumor. Despite advances in the chemotherapy regimen used to treat OS, the 5-year overall survival rates for patients with OS have remained unchanged at 65-70% for the past 20 years. Disease relapse usually occurs in the lungs. Aggressive multidisciplinary treatment with perioperative chemotherapy and surgery can have a therapeutic benefit in the primary tumor, pulmonary metastases remain, and these constitute the most common cause of death in patients with OS. The 5-year overall survival rate is only 30-35% in patients with metastatic disease at diagnosis [2], [3]. Treatment of pulmonary metastatic disease with systemic therapy has been only modestly effective and poses a clinical challenge, highlighting the need for new therapeutic strategies to the currently available treatment regimens
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